Drug depots having different release profiles for reducing, preventing or treating pain and inflammation

ABSTRACT

Effective treatments of pain and/or inflammation are provided. Through the administration of an effective amount of at least analgesic and/or at least one anti-inflammatory agent at or near a target site, one can reduce, prevent or treat inflammation and pain.

BACKGROUND

Pain can adversely affect patients in many different ways. It can keepthe patient from being active, sleeping well, enjoying family andfriends, and from eating. Pain can make the patient feel afraid ordepressed and prevent full participation in general rehabilitationprograms and may even slow recovery.

Proper pain control is of prime importance to anyone treating manydifferent diseases or conditions. Proper pain relief imparts significantphysiological and psychological benefits to the patient. Not only doeseffective pain relief mean a smoother more pleasant recovery (e.g.,mood, sleep, quality of life, etc.) with earlier discharge frommedical/surgical/outpatient facilities, but it may also reduce the onsetof chronic pain syndromes (e.g., fibromyalgia, myalgia, etc.).

Pain serves the important biological function of signaling the presenceof damage or disease within the body and is often accompanied byinflammation (redness, swelling, and/or burning). There are twocategories of pain: acute pain and neuropathic pain. Acute pain refersto pain experienced when tissue is being damaged or is damaged. Acutepain serves at least two physiologically advantageous purposes. First,it warns of dangerous environmental stimuli (such as hot or sharpobjects) by triggering reflexive responses that end contact with thedangerous stimuli. Second, if reflexive responses do not avoid dangerousenvironmental stimuli effectively, or tissue injury or infectionotherwise results, acute pain facilitates recuperative behaviors. Forexample, acute pain associated with an injury or infection encourages anorganism to protect the compromised area from further insult or usewhile the injury or infection heals. Once the dangerous environmentalstimulus is removed, or the injury or infection has resolved, acutepain, having served its physiological purpose, ends. As contrasted toacute pain, in general, neuropathic pain serves no beneficial purpose.Neuropathic pain results when pain associated with an injury orinfection continues in an area once the injury or infection hasresolved.

There are many painful diseases or conditions that require proper painand/or inflammation control, including but not limited to rheumatoidarthritis, osteoarthritis, a spinal disc herniation (i.e., sciatica),carpal tunnel syndrome, lower back pain, lower extremity pain, upperextremity pain, cancer, tissue pain and pain associated with injury orrepair of cervical, thoracic, and/or lumbar vertebrae or intervertebraldiscs, rotator cuff, articular joint, TMJ, tendons, ligaments, muscles,spondilothesis, stenosis, discogenic back pain, and joint pain or thelike.

One particularly painful disease is sciatica. Sciatica is a chronicdisease that often can be very debilitating and may take a terrible tollon those with the disease as well as their families, friends andcaregivers. Sciatica is a very painful disease associated with thesciatic nerve, which runs from the lower part of the spinal cord (thelumbar region), down the back of the leg and to the foot. Sciaticagenerally begins with a herniated disc, which later leads to localimmune system activation. The herniated disc also may damage the nerveroot by pinching or compressing it, leading to additional immune systemactivation in the area.

Another particularly painful disease is spinal stenosis, where there isprogressive constriction of the spinal canal and as it narrows, thenerve elements that reside within it become progressively more crowded.Eventually, the canal dimensions become sufficiently small—so as tosignificantly compress the nerve elements and produce pain, weakness,sensory changes, clumsiness and other manifestation of nervous systemdysfunction. The disease causes lower back pain, lower extremity pain,lower extremity weakness, limitation of mobility and the high disabilityrates that often afflict the elderly.

Spondylolisthesis is another painful disease. Spondylolisthesis is adisplacement disorder of the lumbar or cervical spine, in which onevertebral body is forwardly displaced over another vertebral body.Spondylolisthesis may be caused by a traumatic event or by degenerationof the spine. At times, the displacement disorder is accompanied by orcaused by a fracture or partial collapse of one or more vertebrae ordegeneration of a disc in the spine. Patients who suffer from suchconditions can experience moderate to severe distortion of the thoracicskeletal structure, diminished ability to bear loads, loss of mobility,extreme and debilitating pain, and oftentimes suffer neurologicaldeficits in nerve function.

There has been considerable interest in developing effective treatmentsfor these painful diseases, yet to date current treatments are onlypartially effective.

SUMMARY

Compositions and methods are provided comprising an analgesic and/or ananti-inflammatory agent that are administered in order to treat painand/or inflammation. The pain and/or inflammation may for example be dueto chronic conditions including rheumatoid arthritis, osteoarthritis, aspinal disc herniation (e.g., sciatica), carpal/tarsal tunnel syndrome,lower back pain, lower extremity pain, upper extremity pain, cancer,tissue pain and pain associated with injury or repair of cervical,thoracic, and/or lumbar vertebrae or intervertebral discs, rotator cuff,articular joint, TMJ, tendons, ligaments, muscles, spondilothesis,stenosis, discogenic back pain, and joint pain or the like.

One advantage of the embodiments provided herein is that they utilizeone or more drug depots or one or more drug depot regions having adifferent release profile for the therapeutic agent, which aids in thereduction, prevention or treatment of different diseases.

In various embodiments, one or more regions of the drug depot or one ormore drug depots may be designed to release an initial burst or bolusdose of the analgesic and/or an anti-inflammatory agent, which providesinitial relief in treatment of diseases (e.g., sciatica, spondilothesis,stenosis, etc.), while sustained release regions or drug depots providesustained release of the therapeutic agent over a longer period of time.In this way more effective treatments for different diseases orconditions.

In one embodiment, an implantable drug depot is provided useful forreducing, preventing or treating pain and/or inflammation in a patientin need of such treatment, the implantable drug depot comprising atherapeutically effective amount of an analgesic and/or ananti-inflammatory agent, the depot being implantable at a site beneaththe skin to reduce, prevent or treat pain and/or inflammation, whereinthe drug depot comprises (i) at least one region capable of releasing atherapeutically effective bolus amount of the analgesic and/or theanti-inflammatory agent at a site beneath the skin; and (ii) at leastone region capable of releasing a therapeutically effective amount ofthe analgesic and/or the anti-inflammatory agent over a period of atleast three days.

In another embodiment, a kit is provided comprising a plurality ofimplantable drug depots useful for reducing, preventing or treating painand/or inflammation in a patient in need of such treatment, the kitcomprising a first set of the plurality of drug depots capable ofreleasing a therapeutically effective bolus amount of an analgesicand/or an anti-inflammatory agent or pharmaceutically acceptable saltsthereof at a site beneath the skin and a second set of the plurality ofdrug depots capable of releasing a therapeutically effective amount ofthe analgesic and/or the anti-inflammatory agent or pharmaceuticallyacceptable salts thereof over a period of at least three days. Invarious embodiments, by implanting different sets of drug depot withdifferent release profiles, the need to develop one set of drug depotswith the desired immediate release and sustained release properties isavoided.

In one exemplary embodiment, a method of reducing, preventing ortreating pain and/or inflammation in a patient in need of such treatmentis provided, the method comprising administering a plurality ofimplantable drug depots at or near a target tissue site of the patient,wherein a first set of the plurality of drug depots is capable ofreleasing a therapeutically effective bolus amount of an analgesicand/or an anti-inflammatory agent or pharmaceutically acceptable saltsthereof at a site beneath the skin and a second set of the plurality ofdrug depots is capable of releasing a therapeutically effective amountof the analgesic and/or the anti-inflammatory agent or pharmaceuticallyacceptable salts thereof over a period of at least three days.

In another exemplary embodiment, a plurality of implantable drug depotsis proved that are useful for reducing, preventing or treating painand/or inflammation in a patient in need of such treatment, theplurality of drug depots comprising a first set of one or more drugdepots capable of releasing a therapeutically effective bolus dose of ananalgesic and/or an anti-inflammatory agent or pharmaceuticallyacceptable salts thereof at a site beneath the skin and a second set ofone or more drug depots capable of releasing a therapeutically effectiveamount of the analgesic and/or the anti-inflammatory agent orpharmaceutically acceptable salts thereof over a period of at leastthree days.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 is a schematic drawing illustrating an embodiment of one drugdepot composition having a first region or layer capable of releasing atherapeutically effective bolus amount of the analgesic and/or theanti-inflammatory agent and a second region capable of releasing atherapeutically effective amount of the analgesic and/or theanti-inflammatory agent over a longer period of time.

FIG. 1A is a schematic drawing illustrating an embodiment of one drugdepot composition having a plurality of regions capable of releasing atherapeutically effective bolus amount of the analgesic and/or theanti-inflammatory agent and a region capable of releasing atherapeutically effective amount of the analgesic and/or theanti-inflammatory agent over a longer period of time.

FIG. 2 is a schematic drawing illustrating an embodiment of one drugdepot composition having a plurality of regions capable of releasing atherapeutically effective bolus amount of the analgesic and/or theanti-inflammatory agent and a plurality of regions capable of releasinga therapeutically effective amount of the analgesic and/or theanti-inflammatory agent over a longer period of time.

FIG. 3 is a schematic drawing illustrating an embodiment of a pluralityof drug depots, a first set of drug depots capable of releasing atherapeutically effective bolus amount of the analgesic and/or theanti-inflammatory agent and a second set of drug depots capable ofreleasing a therapeutically effective amount of the analgesic and/or theanti-inflammatory agent over a longer period of time.

FIG. 4 illustrates a number of common locations within a patient thatmay be sites at which inflammation and/or pain occurs and locations atwhich the drug depot containing at least one analgesic agent and atleast one anti-inflammatory agent can be administered locally thereto.

FIG. 5 illustrates a schematic dorsal view of the spine and sites wherethe drug depot containing at least one analgesic agent and at least oneanti-inflammatory agent can be administered locally thereto.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

Analgesic refers to an agent or compound that can reduce, relieve oreliminate pain. Examples of analgesic agents include but are not limitedto acetaminophen, a local anesthetic, such as for example, lidocaine,bupivicaine, ropivacaine, opioid analgesics such as buprenorphine,butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine,fentanyl, alfentanil, sufentanil, hydrocodone, hydromorphone,ketobemidone, levomethadyl, levorphanol, mepiridine, methadone,morphine, nalbuphine, opium, oxycodone, papaveretum, pentazocine,pethidine, phenoperidine, piritramide, dextropropoxyphene, remifentanil,sufentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol,dezocine, eptazocine, flupirtine or a combination thereof.

The phrase “anti-inflammatory agent” refers to an agent or compound thathas anti-inflammatory effects. These agents may remedy pain by reducinginflammation. Examples of anti-inflammatory agents include, but are notlimited to, a statin, sulindac, sulfasalazine, naroxyn, diclofenac,indomethacin, ibuprofen, flurbiprofen, ketoprofen, aclofenac, aloxiprin,aproxen, aspirin, diflunisal, fenoprofen, mefenamic acid, naproxen,phenylbutazone, piroxicam, meloxicam, salicylamide, salicylic acid,desoxysulindac, tenoxicam, ketoralac, clonidine, flufenisal, salsalate,triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone,apazone, cintazone, flufenamic acid, clonixeril, clonixin, meclofenamicacid, flunixin, colchicine, demecolcine, allopurinol, oxypurinol,benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbanehydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrinehydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen,diflumidone sodium, fenamole, flutiazin, metazamide, letimidehydrochloride, nexeridine hydrochloride, octazamide, molinazole,neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin,triflumidate, fenamates (mefenamic acid, meclofenamic acid), nabumetone,celecoxib, etodolac, nimesulide, apazone, gold, tepoxalin;dithiocarbamate, or a combination thereof. Anti-inflammatory agents alsoinclude other compounds such as steroids, such as for example,fluocinolone, cortisol, cortisone, hydrocortisone, fludrocortisone,prednisone, prednisolone, methylprednisolone, triamcinolone,betamethasone, dexamethasone, beclomethasone, fluticasone interleukin-1receptor antagonists, thalidomide (a TNF-α release inhibitor),thalidomide analogues (which reduce TNF-α production by macrophages),bone morphogenetic protein (BMP) type 2 or BMP-4 (inhibitors of caspase8, a TNF-α activator), quinapril (an inhibitor of angiotensin II, whichupregulates TNF-α), interferons such as IL-11 (which modulate TNF-αreceptor expression), and aurin-tricarboxylic acid (which inhibitsTNF-α), guanidinoethyldisulfide, or a combination thereof.

Exemplary anti-inflammatory agents include, for example, naproxen;diclofenac; celecoxib; sulindac; diflunisal; piroxicam; indomethacin;etodolac; meloxicam; ibuprofen; ketoprofen; r-flurbiprofen; mefenamic;nabumetone; tolmetin, and sodium salts of each of the foregoing;ketorolac bromethamine; ketorolac tromethamine; ketorolac acid; cholinemagnesium trisalicylate; rofecoxib; valdecoxib; lumiracoxib; etoricoxib;aspirin; salicylic acid and its sodium salt; salicylate esters of alpha,beta, gamma-tocopherols and tocotrienols (and all their d, 1, andracemic isomers); methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,t-butyl, esters of acetylsalicylic acid; tenoxicam; aceclofenac;nimesulide; nepafenac; amfenac; bromfenac; flufenamate; phenylbutazone,or a combination thereof.

Exemplary steroids include, for example, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, dexamethasone 21-acetate,dexamethasone 21-phosphate di-Na salt, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide or a combination thereof.

Examples of a useful statin for treatment of pain and/or inflammationinclude, but is not limited to, atorvastatin, simvastatin, pravastatin,cerivastatin, mevastatin (see U.S. Pat. No. 3,883,140, the entiredisclosure is herein incorporated by reference), velostatin (also calledsynvinolin; see U.S. Pat. Nos. 4,448,784 and 4,450,171 these entiredisclosures are herein incorporated by reference), fluvastatin,lovastatin, rosuvastatin and fluindostatin (Sandoz XU-62-320),dalvastain (EP Appln. Publn. No. 738510 A2, the entire disclosure isherein incorporated by reference), eptastatin, pitavastatin, orpharmaceutically acceptable salts thereof or a combination thereof. Invarious embodiments, the statin may comprise mixtures of (+)R and (−)-Senantiomers of the statin. In various embodiments, the statin maycomprise a 1:1 racemic mixture of the statin.

Anti-inflammatory agents also include those with anti-inflammatoryproperties, such as, for example, amitriptyline, carbamazepine,gabapentin, pregabalin, clonidine, or a combination thereof.

Unless otherwise specified or apparent from context, where thisspecification and the set of claims that follows refer to ananti-inflammatory agent, the inventors are also referring to apharmaceutically acceptable salt of the anti-inflammatory agentincluding stereoisomers. Pharmaceutically acceptable salts include thosesalt-forming acids and bases that do not substantially increase thetoxicity of the compound. Some examples of potentially suitable saltsinclude salts of alkali metals such as magnesium, calcium, sodium,potassium and ammonium, salts of mineral acids such as hydrochloric,hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuricacids, as well as salts of organic acids such as tartaric, acetic,citric, malic, benzoic, glycollic, gluconic, gulonic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, or the like.

Similarly, when referring to an analgesic agent, unless otherwisespecified or apparent from context, it is understood that the inventorsare also referring to pharmaceutically acceptable salts includingsteroisomers. Pharmaceutically acceptable salts include thosesalt-forming acids and bases that do not substantially increase thetoxicity of the compound. Some examples of potentially suitable saltsinclude salts of alkali metals such as magnesium, calcium, sodium,potassium and ammonium, salts of mineral acids such as hydrochloric,hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuricacids, as well as salts of organic acids such as tartaric, acetic,citric, malic, benzoic, glycollic, gluconic, gulonic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, or the like.

A “drug depot” is the composition in which at least oneanti-inflammatory agent and at least one analgesic agent or thepharmaceutically acceptable salts of either or both are administered tothe body. Thus, a drug depot may comprise a physical structure tofacilitate implantation and retention in a desired site (e.g., a discspace, a spinal canal, a tissue of the patient, particularly at or neara site of surgery, pain, or site of inflammation, etc.). The drug depotalso comprises the drug itself. The term “drug” as used herein isgenerally meant to refer to any substance that alters the physiology ofa patient. The term “drug” may be used interchangeably herein with theterms “therapeutic agent,” “therapeutically effective amount,” and“active pharmaceutical ingredient” or “API.” It will be understood thatunless otherwise specified a “drug” formulation may include more thanone therapeutic agent, wherein exemplary combinations of therapeuticagents include a combination of two or more drugs. The drug provides aconcentration gradient of the therapeutic agent for delivery to thesite. In various embodiments, the drug depot provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 0.1 cm to about 5 cm from the implant site, and comprises at leastone anti-inflammatory agent or its pharmaceutically acceptable salt andat least one analgesic agent or its pharmaceutically acceptable salt.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain, improvement in the condition through musclerelaxation, etc. The dosage administered to a patient can unlessotherwise specified or apparent from context be as single or multipledoses depending upon a variety of factors, including the drug'sadministered pharmacokinetic properties, the route of administration,patient conditions and characteristics (sex, age, body weight, health,size, etc.), extent of symptoms, concurrent treatments, frequency oftreatment and the effect desired. In some embodiments the formulation isdesigned for immediate release. In other embodiments the formulation isdesigned for sustained release. In other embodiments, the formulationcomprises one or more immediate release surfaces and one or more sustainrelease surfaces.

The phrases “sustained release” or “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s). As persons of ordinary skill are aware,sustained release formulations may, by way of example, be created asfilms, slabs, pellets, microparticles, microspheres, microcapsules,spheroids, shaped derivatives and paste. The formulations may be in aform that is suitable for suspension in isotonic saline, physiologicalbuffer or other solution acceptable for injection into a patient.Further, the formulations may be used in conjunction with anyimplantable, insertable or injectable system that a person of ordinaryskill would appreciate as useful in connection with embodiments hereinincluding but not limited to parenteral formulations, microspheres,microcapsules, gels, pastes, implantable rods, pellets, plates orfibers, etc.

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug. Immediate release refers to therelease of drug within a short time period following administration,e.g., generally within a few minutes to about 1 to 2 hours.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc. In various embodiments, the mammal is a human patient.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, e.g., mcg/hr,mcg/day, mg/hr, mg/day, 10% per day for ten days, etc. As persons ofordinary skill know, a release rate profile may be but need not belinear. By way of a non-limiting example, the drug depot may be a pelletthat releases at least one analgesic agent in a bolus dose and at leastone anti-inflammatory agent over a period of time.

Treating or treatment of a disease or condition refers to executing aprotocol, which may include administering one or more drugs to a patient(human, normal or otherwise, or other mammal), in an effort to alleviatesigns or symptoms of the disease. Alleviation can occur prior to signsor symptoms of the disease or condition appearing, as well as aftertheir appearance. Thus, “treating” or “treatment” includes “preventing”or “prevention” of disease or undesirable condition. In addition,“treating” or “treatment” does not require complete alleviation of signsor symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingpain” includes a decrease in pain and does not require completealleviation of pain signs or symptoms, and does not require a cure. Invarious embodiments, reducing pain includes even a marginal decrease inpain. By way of example, the administration of the effective dosages ofat least one analgesic agent and at least one anti-inflammatory agentmay be used to prevent, treat or relieve the symptoms of pain and/orinflammation.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 10cm, or preferably within about 5 cm, or within about 1 cm, or less forexample) thereto. A “targeted delivery system” provides delivery of oneor more drugs depots, gels or depot dispersed in the gel having aquantity of therapeutic agent that can be deposited at or near thetarget site as needed for treatment of pain, inflammation or otherdisease or condition.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

The phrase “pain management medication” includes one or more therapeuticagents that are administered to prevent, alleviate or remove painentirely. These include anti-inflammatory agents, muscle relaxants,analgesics, anesthetics, narcotics, and so forth, and combinationsthereof.

In various embodiments, the depot can be designed to cause an initialburst dose of one or more therapeutic agents within the first 24 hoursafter implantation. “Initial burst” or “burst effect” or “bolus dose” or“pulse dose” refer to the release of therapeutic agent from the depotduring the first 24 hours after the depot comes in contact with anaqueous fluid (e.g., synovial fluid, cerebral spinal fluid, etc.). Theburst effect may be an immediate release. The “burst effect” is believedto be due to the increased release of therapeutic agent from the depot.The initial burst effect or bolus dose may be determined before hand byformulating the depot by calculating the quotient obtained by dividing(i) the effective amount by weight of therapeutic agent to be releasedfrom the depot or region in a predetermined initial period of time afterimplantation of the depot, by (ii) the total amount of therapeutic agentthat is to be delivered from an implanted composition. It is understoodthat the initial burst may vary depending on the shape and surface areaof the implant.

The burst effect with respect to the region or depot, in variousembodiments, can be designed so that a larger initial dose may bereleased over a short period of time to achieve the desired effect. Forexample, if a drug depot is designed to release 15 mg of morphine per 48hours, then the initial burst dose or bolus dose region or depot will bedesigned to release a percentage of the dose within the first 24 hours(e.g., 10 mg of morphine or 66% of the 48 hour dose within 24 hours).Thus, the burst effect of the drug depot or region releases moretherapeutic agent than the sustained release region or depot.

A region or depot that utilizes a burst effect or bolus dose willrelease more therapeutic agent (e.g., analgesic and/oranti-inflammatory) than the sustained release region or depot. Forexample, particularly with painful chronic conditions includingrheumatoid arthritis, osteoarthritis, a spinal disc herniation (e.g.,sciatica), carpal/tarsal tunnel syndrome, lower back pain, lowerextremity pain, upper extremity pain, cancer, tissue pain and painassociated with injury or repair of cervical, thoracic, and/or lumbarvertebrae or intervertebral discs, rotator cuff, articular joint, TMJ,tendons, ligaments, muscles, spondilothesis, stenosis, discogenic backpain, and joint pain or the like, the initial burst effect of the drugdepot or region of the drug depot will be advantageous as it willprovide more immediate pain and/or inflammation relief as a bolus doseof drug will be released at or near the target tissue site and providethe desired reducing, or alleviation of signs or symptoms of pain and/orinflammation. For example, the drug depot or region of the drug depotmay release 51%, 52%, 53%, 54%, 55%, % 56%, 57%, 58%, 59%, 60%, 61%,62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the dailydose within the first one to twelve hours to reduce, prevent or treatpain and/or inflammation. The pain and/or inflammation may also be dueto surgery.

The drug depot comprising at least one analgesic agent or itspharmaceutically acceptable salt and at least one anti-inflammatoryagent or its pharmaceutically acceptable salt may be co-administeredwith a muscle relaxant. Co-administration may involve administering atthe same time in separate drug depots or formulating together in thesame drug depot.

Exemplary muscle relaxants include by way of example and not limitation,alcuronium chloride, atracurium bescylate, baclofen, carbolonium,carisoprodol, chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine,dantrolene, decamethonium bromide, fazadinium, gallamine triethiodide,hexafluorenium, meladrazine, mephensin, metaxalone, methocarbamol,metocurine iodide, pancuronium, pridinol mesylate, styramate,suxamethonium, suxethonium, thiocolchicoside, tizanidine, tolperisone,tubocuarine, vecuronium, or combinations thereof.

The drug depot may also comprise other therapeutic agents or activeingredients in addition to the at least one analgesic agent or itspharmaceutically acceptable salt and at least one anti-inflammatoryagent or its pharmaceutically acceptable salt. Suitable additionaltherapeutic agents include, but are not limited to, integrinantagonists, alpha-4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, CTLA4-Ig agonists/antagonists(BMS-188667), CD40 ligand antagonists, Humanized anti-IL-6 mAb (MRA,Tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics Inc.), anti-IL2Rantibodies (daclizumab, basilicimab), ABX (anti IL-8 antibodies),recombinant human IL-10, or HuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents that may be co-administered with theanti-inflammatory agent and analgesic agent include IL-1 inhibitors,such Kineret® (anakinra) which is a recombinant, non-glycosylated formof the human inerleukin-1 receptor antagonist (IL-1Ra), or AMG 108,which is a monoclonal antibody that blocks the action of IL-1.Therapeutic agents also include excitatory amino acids such as glutamateand aspartate, antagonists or inhibitors of glutamate binding to NMDAreceptors, AMPA receptors, and/or kainate receptors. It is contemplatedthat where desirable a pegylated form of the above may be used. Examplesof other therapeutic agents include NF kappa B inhibitors such asglucocorticoids, antioxidants, such as dilhiocarbamate.

Specific examples of additional therapeutic agents suitable for useinclude, but are not limited to, an anabolic growth factor oranti-catabolic growth factor, analgesic agent, or an osteoinductivegrowth factor or a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Suitable analgesic agents include, but are not limited to,acetaminophen, bupivicaine, opioid analgesics such as amitriptyline,carbamazepine, gabapentin, pregabalin, clonidine, opioid analgesics or acombination thereof. Opioid analgesics include, alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol or acombination thereof.

For each of the anti-inflammatory agents and analgesic agents, in someembodiments, the release of each compound may be for at least one, atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine, at least ten, at leasteleven, at least twelve, at least thirteen, at least fourteen, or atleast fifteen days, or longer.

Sulfazalazine

In one embodiment, the anti-inflammatory agent comprises sulfasalazine.Sulfasalazine is also known as6-oxo-3-((4-(pyridin-2-ylsulfamoyl)phenyl)hydrazinylidene]cyclohexa-1,4-diene-1-carboxylicacid. Sulfasalazine or a pharmaceutically acceptable salt thereof isavailable from various pharmaceutical manufacturers.

In one embodiment, the dosage of sulfasalazine is from approximately0.005 μg/day to approximately 3000 mg/day. Additional dosages ofsulfasalazine include from approximately 0.005 μg/day to approximately2000 mg/day; approximately 0.005 μg/day to approximately 1000 mg/day;approximately 0.005 μg/day to approximately 100 mg/day; approximately0.005 μg/day to approximately 1 mg/day; approximately 0.005 μg/day toapproximately 80 μg/day; approximately 0.01 μg/day to approximately 70μg/day; approximately 0.01 μg/day to approximately 65 μg/day;approximately 0.01 μg/day to approximately 60 μg/day; approximately 0.01μg/day to approximately 55 μg/day; approximately 0.01 μg/day toapproximately 50 μg/day; approximately 0.01 μg/day to approximately 45μg/day; approximately 0.01 to approximately 40 μg/day; approximately0.025 μg/day to approximately 35 μg/day; approximately 0.025 μg/day toapproximately 30 μg/day; approximately 0.025 μg/day to approximately 25μg/day; approximately 0.025 μg/day to approximately 20 μg/day; andapproximately 0.025 μg/day to approximately 15 μg/day. In anotherembodiment, the dosage of sulfasalazine is from approximately 0.05μg/day to approximately 15 μg/day. In another embodiment, the dosage ofsulfasalazine is from approximately 0.05 to approximately 10 μg/day. Thedrug depot may release an initial burst dose or bolus dose or pulse doseor immediate release dose based on the daily dosage. The drug depot mayrelease a longer sustained release dose based on the daily dosage.

Sulindac

In one embodiment, the anti-inflammatory agent comprises sulindac.Sulindac, also known as2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)-methylidene]inden-1-yl]-aceticacid may be represented by the formula C₂₀H₁₇FO₃S. Sulindac or apharmaceutically acceptable salt thereof is available from variouspharmaceutical manufacturers.

The dosage of sulindac may be from approximately 0.001 μg/day toapproximately 400 mg/day. Additional dosages of sulindac include fromapproximately 0.001 μg/day to approximately 200 mg/day; approximately0.001 μg/day to approximately 100 mg/day; approximately 0.001 μg/day toapproximately 1 mg/day; approximately 0.001 to approximately 500 μg/day;approximately 0.001 to approximately 100 μg/day; approximately 0.025 toapproximately 75 μg/day; approximately 0.025 to approximately 65 μg/day;approximately 0.025 to approximately 60 μg/day; approximately 0.025 toapproximately 55 μg/day; approximately 0.025 to approximately 50 μg/day;approximately 0.025 to approximately 45 μg/day; approximately 0.025 toapproximately 40 μg/day; approximately 0.025 to approximately 35 μg/day;approximately 0.005 to approximately 30 μg/day; approximately 0.005 toapproximately 25 μg/day; approximately 0.005 to approximately 20 μg/day;and approximately 0.005 to approximately 15 μg/day. In anotherembodiment, the dosage of sulindac is from approximately 0.01 toapproximately 15 μg/day. In another embodiment, the dosage of sulindacis from approximately 0.01 to approximately 10 μg/day. In anotherembodiment, the dosage of sulindac is from approximately 0.01 toapproximately 5 μg/day. In another embodiment, the dosage of sulindac isfrom approximately 0.01 to approximately 20 μg/day. In anotherembodiment, the sulindac is administered in a drug depot that releases9.6 μg/day. The drug depot may release an initial burst dose or bolusdose or pulse dose or immediate release dose based on the daily dosage.The drug depot may release a longer sustained release dose based on thedaily dosage.

Clonidine

In one embodiment, the anti-inflammatory agent is clonidine, alsoreferred to as 2,6-dichloro-N-2-imidazolidinyldenebenzenamine. Clonidineor a pharmaceutically acceptable salt thereof is available from variouspharmaceutical manufactures. In various embodiments, the clonidine maybe in free acid form or the HCL.

The dosage may be from approximately 0.0005 to approximately 100μg/kg/day. Additional dosages of clonidine include from approximately0.0005 to approximately 95 μg/kg/day; approximately 0.0005 toapproximately 90 μg/kg/day; approximately 0.0005 to approximately 85μg/kg/day; approximately 0.0005 to approximately 80 μg/kg/day;approximately 0.0005 to approximately 75 μg/kg/day; approximately 0.001to approximately 70 μg/kg/day; approximately 0.001 to approximately 65μg/kg/day; approximately 0.001 to approximately 60 μg/kg/day;approximately 0.001 to approximately 55 μg/kg/day; approximately 0.001to approximately 50 μg/kg/day; approximately 0.001 to approximately 45μg/kg/day; approximately 0.001 to approximately 40 μg/kg/day;approximately 0.001 to approximately 35 μg/kg/day; approximately 0.0025to approximately 30 μg/kg/day; approximately 0.0025 to approximately 25μg/kg/day; approximately 0.0025 to approximately 20 μg/kg/day; andapproximately 0.0025 to approximately 15 μg/kg/day. In anotherembodiment, the dosage of clonidine is from approximately 0.005 toapproximately 15 μg/kg/day. In another embodiment, the dosage ofclonidine is from approximately 0.005 to approximately 10 μg/kg/day. Inanother embodiment, the dosage of clonidine is from approximately 0.005to approximately 5 μg/kg/day. In another embodiment, the dosage ofclonidine is from approximately 0.005 to 2.5μ/kg/day. In someembodiments, the amount of clonidine is between 40 and 600 μg/day. Insome embodiments, the amount of clonidine is between 200 and 400 μg/day.The drug depot may release an initial burst dose or bolus dose or pulsedose or immediate release dose based on the daily dosage. The drug depotmay release a longer sustained release dose based on the daily dosage.

Fluocinolone

In one embodiment, the anti-inflammatory agent comprises fluocinoloneacetonide. Fluocinolone is available from various pharmaceuticalmanufacturers.

Fluocinolone is available from various pharmaceutical manufacturers. Thedosage of fluocinolone may be from approximately 0.0005 to approximately100 μg/day. Additional dosages of fluocinolone include fromapproximately 0.0005 to approximately 50 μg/day; approximately 0.0005 toapproximately 25 μg/day; approximately 0.0005 to approximately 10μg/day; approximately 0.0005 to approximately 5 μg/day; approximately0.0005 to approximately 1 μg/day; approximately 0.005 to approximately0.75 μg/day; approximately 0.0005 to approximately 0.5 μg/day;approximately 0.0005 to approximately 0.25 μg/day; approximately 0.0005to approximately 0.1 μg/day; approximately 0.0005 to approximately 0.075μg/day; approximately 0.0005 to approximately 0.05 μg/day; approximately0.001 to approximately 0.025 μg/day; approximately 0.001 toapproximately 0.01 μg/day; approximately 0.001 to approximately 0.0075μg/day; approximately 0.001 to approximately 0.005 μg/day; approximately0.001 to approximately 0.025 μg/day; and 0.002 to approximately 0.025μg/day. In another embodiment, the dosage of fluocinolone is fromapproximately 0.001 to approximately 15 μg/day. In another embodiment,the dosage of fluocinolone is from approximately 0.001 to approximately10 μg/day. In another embodiment, the dosage of fluocinolone is fromapproximately 0.001 to approximately 5 μg/day. In another embodiment,the dosage of fluocinolone is from approximately 0.001 to 2.5 μg/day. Insome embodiments, the amount of fluocinolone is between 40 and 600μg/day. In some embodiments, the amount of fluocinolone is between 200and 400 μg/day. Dosing formulations may be prepared to contain asufficient amount of the active ingredient to enable the desired aboutof compound to be release over the desired amount of time.

In some embodiments, there is sufficient fluocinolone such that thefluocinolone is released at a rate of 2-3 μg per day for a period of atleast three days. In some embodiments, this release rate continues for,at least ten days, at least fifteen days, at least twenty-five days, atleast thirty days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days. Thedrug depot may release an initial burst dose or bolus dose or pulse doseor immediate release dose based on the daily dosage. The drug depot mayrelease a longer sustained release dose based on the daily dosage.

Dexamethasone

In one embodiment of the present invention, the anti-inflammatory agentis dexamethasone, also referred to as8S,9R,10S,11S,13S,14S,16R,17R)-9-Fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16octahydrocyclopenta[a]-phenanthren-3-one), or a pharmaceuticallyacceptable salt thereof, which is available from various manufacturers.

In various embodiments, dexamethasone may be released from the depot ata dose of about 10 pg to about 80 mg/day, about 2.4 ng/day to about 50mg/day, about 50 ng/day to about 2.5 mg/day, about 250 ng/day to about250 ug/day, about 250 ng/day to about 50 ug/day, about 250 ng/day toabout 25 ug/day, about 250 ng/day to about 1 ug/day, about 300 ng/day toabout 750 ng/day or about 0.50 ug/day. In various embodiments, the dosemay be about 0.01 to about 10 μg/day or about 1 ng to about 120 μg/day.The drug depot may release an initial burst dose or bolus dose or pulsedose or immediate release dose based on the daily dosage. The drug depotmay release a longer sustained release dose based on the daily dosage.

In one exemplary embodiment, the dexamethasone is dexamethasone acetate,or sodium phosphate.

Lovastatin

In one exemplary embodiment, the anti-inflammatory agent compriseslovastatin. Lovastatin is a statin that may be obtained from variousmanufacturers in various forms (e.g., injection, powder, etc.). Forexample, lovastatin may be obtained from Merck as Mevacor® (see U.S.Pat. No. 4,231,938, the entire disclosure is herein incorporated byreference). Suitable pharmaceutically acceptable salts of lovastatininclude one or more compounds derived from bases such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts oflovastatin include lithium, calcium, hemicalcium, sodium, potassium,magnesium, aluminum, ferrous or ferric salts thereof or a combinationthereof.

In various embodiments, the therapeutically effective amount oflovastatin comprises from about 0.1 pg to about 2000 mg, for example,0.1 ng to 1000 mg, 500 mg, 100 mg, 50 mg, 25 mg, 10 mg, 1 mg, 50 μg, 25μg, 10 μg, 1 μg, 500 ng, 250 ng, 100 ng, 75 ng, 50 ng, 25 ng, 15 ng, 10ng, 5 ng, or 1 ng of lovastatin per day. In various embodiments, thedosage may be, for example from about 3 ng/day to 0.3 μg/day. The drugdepot may release an initial burst dose or bolus dose or pulse dose orimmediate release dose based on the daily dosage. The drug depot mayrelease a longer sustained release dose based on the daily dosage.

Morphine

In one embodiment of the present invention, the analgesic agent ismorphine. Morphine is also referred to as(5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol and has thechemical formula C₁₇H₁₉NO₃. Morphine and a pharmaceutically acceptablesalt thereof is available from various manufacturers. In one exemplaryembodiment, the morphine comprises morphine sulfate or hydrochloride.

The dosage of the morphine may be from 0.1 mg to 1000 mg per day. Forexample, the dosage of morphine may be for example, 0.1 mg to 2 mg, 5mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200mg of morphine per day. The drug depot may release an initial burst doseor bolus dose or pulse dose or immediate release dose based on the dailydosage. The drug depot may release a longer sustained release dose basedon the daily dosage.

Tramadol

In one embodiment, the analgesic agent is tramadol. Tramadol is alsoreferred to as(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanolhydrochloride and has the chemical formula C₁₆H₂₅NO₂. Tramadol or apharmaceutically acceptable salt thereof is available from variousmanufacturers. In one embodiment, the tramadol comprises tramadol HCL.

The dosage of the tramadol may be from 0.01 mg to 500 mg per day. Forexample, the dosage of tramadol may be for example, 0.1 mg to 2 mg, 5mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200mg, or 500 mg of tramadol per day.

In one embodiment, the drug depot contains sufficient tramadol torelease between 2.5 and 30 mg/kg/day. In another embodiment the drugdepot contains sufficient tramadol to release between 3 and 27.5mg/kg/day. The drug depot may release an initial burst dose or bolusdose or pulse dose or immediate release dose based on the daily dosage.The drug depot may release a longer sustained release dose based on thedaily dosage.

The at least one anti-inflammatory agent and at least one analgesicagent may also be administered with non-active ingredients. Thesenon-active ingredients may have multi-functional purposes including thecarrying, stabilizing and controlling the release of the therapeuticagent(s). The sustained release process, for example, may be by asolution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable. The term “solid” is intended to mean a rigid material,while “semi-solid” is intended to mean a material that has some degreeof flexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to (for biodegradablecomponents) or greater than (for non-biodegradable components) theplanned period of drug delivery. For example, the depot material mayhave a melting point or glass transition temperature close to or higherthan body temperature, but lower than the decomposition or degradationtemperature of the therapeutic agent. However, the pre-determinederosion of the depot material can also be used to provide for slowrelease of the loaded therapeutic agent(s).

In various embodiments, the drug depot may not be biodegradable orcomprise material that is not biodegradable. Non-biodegradable polymersinclude, but are not limited to, various cellulose derivatives(carboxymethyl cellulose, cellulose acetate, cellulose acetatepropionate, ethyl cellulose, hydroxypropyl methyl cellulose,hydroxyalkyl methyl celluloses, and alkyl celluloses), silicon andsilicon-based polymers (such as polydimethylsiloxane),polyethylene-co-(vinyl acetate), poloxamer, polyvinylpyrrolidone,poloxamine, polypropylene, polyamide, polyacetal, polyester, polyethylene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or“Teflon™”), styrene butadiene rubber, polyethylene, polypropylene,polyphenylene oxide-polystyrene, poly-α-chloro-p-xylene,polymethylpentene, polysulfone, non-degradable ethylene-vinyl acetate(e.g., ethylene vinyl acetate disks and poly(ethylene-co-vinylacetate)), and other related biostable polymers or combinations thereof.

The drug depot may comprise non-resorbable polymers as well. Thesenon-resorbable polymers can include, but are not limited to, delrin,polyurethane, copolymers of silicone and polyurethane, polyolefins (suchas polyisobutylene and polyisoprene), acrylamides (such as polyacrylicacid and poly(acrylonitrile-acrylic acid)), neoprene, nitrile, acrylates(such as polyacrylates, poly(2-hydroxy ethyl methacrylate), methylmethacrylate, 2-hydroxyethyl methacrylate, and copolymers of acrylateswith N-vinyl pyrrolidone), N-vinyl lactams, polyacrylonitrile,glucomannan gel, vulcanized rubber and combinations thereof. Examples ofpolyurethanes include thermoplastic polyurethanes, aliphaticpolyurethanes, segmented polyurethanes, hydrophilic polyurethanes,polyether-urethane, polycarbonate-urethane and siliconepolyether-urethane. Typically, the non-degradable drug depots may needto be removed.

In some instance, it may be desirable to avoid having to remove the drugdepot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioabsorbable, and/or abiodegradable biopolymer that may provide immediate release, orsustained release of the at least one analgesic agent and at least oneanti-inflammatory agent. Examples of suitable sustained releasebiopolymers include but are not limited to poly (alpha-hydroxy acids),poly (lactide-co-glycolide) (PLGA or PLG), polylactide (PLA),polyglycolide (PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids), polyorthoesters, polyaspirins, polyphosphagenes,collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans,gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D,L-lactide, orL-lactide, poly(glycolide-,-caprolactone), ,-caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly (N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate) or combinations thereof. As persons of ordinaryskill are aware, mPEG may be used as a plasticizer for PLGA, but otherpolymers/excipients may be used to achieve the same effect. mPEG impartsmalleability to the resulting formulations.

Where different combinations of polymers are used (bi, tri (e.g.,PLGA-PEO-PLGA) or terpolymers), they may be used in different molarratios, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. Forexample, for a 130-day release drug depot, the polymer make up is 50:50PLGA to 100 PLA. The molecular weight range is 0.45 to 0.8 dI/g.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolic acid) (PLA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolic acid) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousother embodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer beingpolyglycolide.

In some embodiments, the biodegradable polymer comprises at least 10 wt%, at least 50 wt. %, at least 60 wt. %, at least 70 wt. %, at least 80wt. %, at least 85 wt. %, at least 90 wt. %, at least 95 wt. %, or atleast 99 wt. % of the formulation. In some embodiments, the at least onebiodegradable polymer and the analgesic and the anti-inflammatory arethe only components of the pharmaceutical formulation.

In some embodiments, at least 75% of the particles have a size fromabout 1 micrometer to about 250 micrometers. In some embodiments, atleast 85% of the particles have a size from about 1 micrometer to about100 micrometers. In some embodiments, at least 95% of the particles havea size from about 1 micrometer to about 30 micrometers. In someembodiments, all of the particles have a size from about 1 micrometer toabout 30 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 5 micrometer to about 20 micrometers. In some embodiments, atleast 85% of the particles have a size from about 5 micrometers to about20 micrometers. In some embodiments, at least 95% of the particles havea size from about 5 micrometer to about 20 micrometers. In someembodiments, all of the particles have a size from about 5 micrometer toabout 250 micrometers.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfite,sodium bisulfate, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. Typically, any such inactivematerials will be present within the range of 0-75 wt %, and moretypically within the range of 0-30 wt %. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a pellet, a sphere, a cylinder such as a rod or fiber, aflat surface such as a disc, film or sheet, or the like. Flexibility maybe a consideration so as to facilitate placement of the drug depot. Invarious embodiments, the drug depot can be different sizes, for example,the drug depot may be a length of from about 0.5 mm to 5 mm and have adiameter of from about 0.01 to about 2 mm. In various embodiments, thedrug depot may have a layer thickness of from about 0.005 to 1.0 mm,such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium phosphate, and/or metal beads or particles. In variousembodiments, the radiographic marker could be a spherical shape or aring around the depot.

FIG. 1 is a schematic drawing illustrating an embodiment of one drugdepot 10 composition having a first region or layer 12 capable ofreleasing a therapeutically effective burst amount or bolus dose orpulse dose or immediate release of the analgesic and/or theanti-inflammatory agent as the depot comes in contact with the bodilyfluid and the layer or region degrades and releases the therapeuticagent(s). In this way, short-term relief of pain and/or inflammation canbe provided to the patient. A second layer or region (shown as the core)of the depot shown as 14 is capable of releasing a therapeuticallyeffective amount of the analgesic and the anti-inflammatory agent over alonger period of time (e.g, at least 3 days to 6 months) as this regionor layer comes into contact with bodily fluid.

Although the initial burst region or layer is shown separately from thesustained release layer, it will be understood that the initial burstregion or layer may be combined with the sustained release region orlayer and thus when fluid contacts the depot each layer will release atdifferent release rates. It will also be understood that, although thedepot is shown with two layers or regions (12 and 14), the depot maycomprise one or multiple layers or regions (e.g., two, three, four,five, six, seven, eight, nine ten, etc.). For example, a first immediaterelease layer or region may be disposed on a first sustained releaselayer and a second immediate release layer may be disposed on the firstsustained release layer, and so on. It will also be understood that thedepot may be formed from a mixture of a sustained release formulationwith a burst release formulation that are combined together.

For example, the depot may be formed from separate different micelles(one or more bolus release micelle and one or more sustained releasemicelles) having different release profiles that are combined together.In various embodiments, the plurality of depots may comprisebiodegradable therapeutic particles dispersed within a gel and as thegel degrades, the therapeutic particles are released.

FIG. 1A is a schematic drawing illustrating an embodiment of one drugdepot composition 10 having a plurality of regions 12 capable ofreleasing a therapeutically effective burst amount or bolus dose orpulse dose or immediate release of the analgesic and/or theanti-inflammatory agent as the region degrades when it comes intocontact with bodily fluid. Region 14 is capable of releasing atherapeutically effective amount of the analgesic and theanti-inflammatory agent over a longer period of time (sustained releaseover a longer period of time) as the region degrades when it comes intocontact with bodily fluid.

FIG. 2 is a schematic drawing illustrating an embodiment of one drugdepot composition having a plurality of regions 12 capable of releasinga therapeutically effective a burst amount or bolus dose or pulse doseor immediate release of the analgesic and/or the anti-inflammatoryagent, when bodily fluids come in contact with the region. A pluralityof regions 14 are provided and are capable of releasing atherapeutically effective amount of the analgesic and theanti-inflammatory agent over a longer period of time, when bodily fluidcome in contact with these regions. The regions 12 and 14 may be housedin the drug depot housing 16, which also may be biodegradable as well asthe regions.

FIG. 3 is a schematic drawing illustrating an embodiment of a pluralityof drug depots, a first set of drug depots 12 capable of releasing atherapeutically effective burst amount or bolus dose or pulse dose orimmediate release of the analgesic and/or the anti-inflammatory agentand a plurality of regions 14 capable of releasing a therapeuticallyeffective amount of the analgesic and the anti-inflammatory agent over alonger period of time (sustained release). Thus, in this embodiment,there is a set of drug depots. One set may have a burst release or bolusrelease or pulse release or immediate release and the other set may besustained release over a longer period of time. Thus, the first andsecond depot set have different release profiles. In this embodiment, anumber of pellets for different diseases/conditions (e.g., sciatica,post-operative pain etc.) with various drug release kinetics, some withfast release and other with slow release can be implanted together thusavoiding the need for one drug depot with complicated release kinetics.In conditions, for example, post-operative pain, one can implant 3-5strips at the surgical site in one patient at a time to reduce, preventor treat post-operative pain.

A strategy of triangulation may be effective when administering thesemultiple depot pharmaceutical formulations. Thus, a plurality (at leasttwo, at least three, at least four, at least five, at least six, atleast seven, etc.) drug depots comprising the pharmaceuticalformulations may be placed around the target tissue site (also known asthe pain generator or pain generation site) such that the target tissuesite falls within a region that is either between the formulations whenthere are two, or within an area whose perimeter is defined by a set ofplurality of formulations.

Various factors can be adjusted to achieve the initial burst oftherapeutic agent release. First, the initial burst can be controlled byfactors related to the property of the depot, such as the waterimmiscibility of the solvent, polymer/solvent ratio, and the property ofthe polymer. The extent of water immiscibility of the solvent used inthe depot affects that rate aqueous body fluid can penetrate the depotto release the therapeutic agent. Generally, higher water solubilityleads to a higher initial burst while water immiscibility leads to alower initial burst or slower release (sustained release) of thetherapeutic agent.

Suitable solvents that can be used to control initial burst release orsustained release include, but are not limited to, methyl benzoate,ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate,isobutyl benzoate, sec-butyl benzoate, tert-butyl benzoate, isoamylbenzoate, benzyl benzoate, water, alcohol, low molecular weight PEG(less than 1,000 MW), triacetin, diacetin, tributyrin, triethyl citrate,tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate,triethylglycerides, triethyl phosphate, diethyl phthalate, diethyltartrate, mineral oil, polybutene, silicone fluid, glycerin, ethyleneglycol, octanol, ethyl lactate, propylene glycol, propylene carbonate,ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide,N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate,ethyl acetate, methyl ethyl ketone, dimethylformamide, glycofurol,dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide,oleic acid, 1-dodecylazacyclo-heptan-2-one, or mixtures thereof. Thesolvent can be mixed, in various embodiments, with the therapeutic agentand/or polymers to obtain the desired release profile.

The depot may have pore forming agents, which include biocompatiblematerials that when contacted with body fluids dissolve, disperse ordegrade to create pores or channels in the polymer matrix. Typically,organic and non-organic materials that are water soluble such as sugars(e.g., sucrose, dextrose), water soluble salts (e.g., sodium chloride,sodium phosphate, potassium chloride, and sodium carbonate), watersoluble solvents such as N-methyl-2-pyrrolidone and polyethylene glycoland water soluble polymers (e.g., carboxymethylcellulose,hydroxypropyl-cellulose, and the like) can conveniently be used as poreformers. Such materials may be present in amounts varying from about0.1% to about 100% of the weight of the polymer, but will typically beless than 50% and more typically less than 10-20% of the weight ofpolymer.

Further, varying the molecular weight of the polymer in the depot, oradjusting the molecular weight distribution of the polymer material inthe depot vehicle can affect the initial burst and the release rate oftherapeutic agent from the depot. Generally, a higher molecular weightpolymer renders a lower initial burst and slower release rate of thetherapeutic agent. The polymers may have different end groups such asacid and ester end groups. As persons of ordinary skill in the art areaware, implantable elastomeric depot compositions having a blend ofpolymers with different end groups are used the resulting formulationwill have a lower burst index and a regulated duration of delivery. Forexample, one may use polymers with acid (e.g., carboxylic acid) andester end groups (e.g., methyl of ethyl ester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer) there willbe a resulting depot composition having a regulated burst index andduration of delivery. For example, a depot composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot composition having apolymer with a L/G ratio of 65:35 may have a duration of delivery ofabout two months; a depot composition having a polymer with a L/G ratioof 75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot composition having a polymerratio with a L/G ratio of 85:15 may have a duration of delivery of aboutfive months; a depot composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% may have a duration of deliveryof about one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% may have a duration months upto six months. In general, increasing the G content relative to the CLcontent shortens the duration of delivery whereas increasing the CLcontent relative to the G content lengthens the duration of delivery.Thus, among other things, depot compositions having a blend of polymershaving different molecular weights, end groups and comonomer ratios canbe used to create a depot formulation having a lower burst index and aregulated duration of delivery.

Factors such as the particle size, the disintegration of theparticulates, the morphology of the particulates (e.g., whether poresare present in the particulates before implanting or can be formedeasily by body fluid attack), coatings, complex formation by thetherapeutic agent and the strength of complex bond, can be manipulatedto achieve the desired low initial burst and release rate.

In various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-ε-caprolactone,D,L-lactide-glycolide-ε-caprolactone, glycolide-caprolactone or acombination thereof.

Gel

In various embodiments, the gel has a pre-dosed viscosity in the rangeof about 1 to about 500 centipoise (cps), 1 to about 200 cps, or 1 toabout 100 cps. After the gel is administered to the target site, theviscosity of the gel will increase and the gel will have a modulus ofelasticity (Young's modulus) in the range of about 1×10⁴ to about 6×10⁵dynes/cm², or 2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵dynes/cm².

In one embodiment, a depot comprises an adherent gel comprising at leastone analgesic agent and at least one anti-inflammatory agent that isevenly distributed throughout the gel. The gel may be of any suitabletype, as previously indicated, and should be sufficiently viscous so asto prevent the gel from migrating from the targeted delivery site oncedeployed; the gel should, in effect, “stick” or adhere to the targetedtissue site. The gel may, for example, solidify upon contact with thetargeted tissue or after deployment from a targeted delivery system. Thetargeted delivery system may be, for example, a syringe, a catheter,needle or cannula or any other suitable device. The targeted deliverysystem may inject the gel into or on the targeted tissue site. Thetherapeutic agent may be mixed into the gel prior to the gel beingdeployed at the targeted tissue site. In various embodiments, the gelmay be part of a two-component delivery system and when the twocomponents are mixed, a chemical process is activated to form the geland cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×10⁴ to about 3×10⁵dynes/cm², or 2×10⁴ to about 2×10⁵ dynes/cm², or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×10⁴ to about 2×10⁶ dynes/cm², or 1×10⁵ to about 7×10⁵ dynes/cm²,or 2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances.

In various embodiments, the molecular weight of the gel can be varied byany one of the many methods known in the art. The choice of method tovary molecular weight is typically determined by the composition of thegel (e.g., polymer versus non-polymer). For example in variousembodiments, when the gel comprises one or more polymers, the degree ofpolymerization can be controlled by varying the amount of polymerinitiators (e.g. benzoyl peroxide), organic solvents or activator (e.g.DMPT), crosslinking agents, polymerization agent, and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel, which includes a high molecular weight polymer, tends tocoagulate or solidify more quickly than a polymeric composition, whichincludes a low-molecular weight polymer. Polymeric gel formulations,which include high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel, which include a low-molecularweight polymer.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to a high viscosity, similar tothat of a paste, depending on the molecular weight and concentration ofthe polymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and longer degradationtime). Typically, a gel with a high molecular weight provides a strongermatrix and the matrix takes more time to degrade. In contrast, a gelwith a low molecular weight degrades more quickly and provides a softermatrix. In various embodiments, the gel has a molecular weight, as shownby the inherent viscosity, from about 0.10 dL/g to about 1.2 dL/g orfrom about 0.10 dL/g to about 0.40 dL/g.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, from about 15 cps to about 75 cps at room temperature. The gelmay optionally have a viscosity enhancing agent such as, for example,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose and salts thereof, Carbopol,poly-(hydroxyethylmethacrylate), poly-(methoxyethylmethacrylate),poly(methoxyethoxyethyl methacrylate), polymethylmethacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900,PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinationsthereof.

In various embodiments, when a polymer is employed in the gel, thepolymeric composition includes about 10 wt % to about 90 wt % or about30 wt % to about 60 wt % of the polymer.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biodegradable and biocompatible forin vivo applications. Suitable hydrogels include natural hydrogels, suchas, for example, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagents into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with at least one analgesic agent and at leastone anti-inflammatory agent. In one embodiment, the microspheres providefor a sustained release of the at least one analgesic agent and at leastone anti-inflammatory agent. In yet another embodiment, the gel, whichis biodegradable, prevents the microspheres from releasing the at leastone analgesic agent and at least one anti-inflammatory agent; themicrospheres thus do not release the at least one analgesic agent and atleast one anti-inflammatory agent until they have been released from thegel. For example, a gel may be deployed around a target tissue site(e.g., a nerve root). Dispersed within the gel are a plurality ofmicrospheres that encapsulate the desired therapeutic agent. Certain ofthese microspheres degrade once released from the gel, thus releasingthe at least one analgesic agent and at least one anti-inflammatoryagent. The analgesic agents and anti-inflammatory agents may be placedinto separate microspheres and then the microspheres combined, or theactive ingredients can first be combined and then placed into themicrospheres together.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse the atleast one analgesic agent and at least one anti-inflammatory agent. Insome embodiments, the diameter of the microspheres range from about 10microns in diameter to about 200 microns in diameter. In someembodiments they range from about 20 to 120 microns in diameters.Methods for making microspheres include but are not limited to solventevaporation, phase separation and fluidized bed coating. In somesituations, this may be desirable; in others, it may be more desirableto keep the at least one analgesic agent and at least oneanti-inflammatory agent tightly constrained to a well-defined targetsite.

The present invention also contemplates the use of adherent gels to soconstrain dispersal of the therapeutic agent. These gels may bedeployed, for example, in a disc space, in a spinal canal, or insurrounding tissue.

Cannulas and Needles

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 25 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, calcium phosphate,and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, x-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

Sterilization

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including, but not limited to, gassterilization, such as, for example, with ethylene oxide or steamsterilization.

Kits

In various embodiments, a kit is provided comprising a plurality ofimplantable drug depots useful for reducing, preventing or treating painand inflammation in a patient in need of such treatment, the kitcomprising a first set of the plurality of drug depots capable ofreleasing a therapeutically effective bolus dose of an analgesic and/oran anti-inflammatory agent or pharmaceutically acceptable salts thereofat a site beneath the skin and a second set of the plurality of drugdepots capable of releasing a therapeutically effective amount of theanalgesic and the anti-inflammatory agent or pharmaceutically acceptablesalts thereof over a period of at least three days.

The kit may include additional parts along with the drug depot and/ormedical device combined together to be used to implant the drug depots(e.g., pellets, gel, etc.). The kit may include the drug depot device ina first compartment. The second compartment may include a canisterholding the drug depots or each drug depot with a different releaseprofile may be labeled and placed in a different compartment (e.g.,bolus dose depot compartment, sustained release depot compartment, etc.)and any other instruments needed for the localized drug delivery. Athird compartment may include gloves, drapes, wound dressings and otherprocedural supplies for maintaining sterility of the implanting process,as well as an instruction booklet. A fourth compartment may includeadditional cannulas and/or needles. Each tool may be separately packagedin a plastic pouch that is radiation sterilized. A fifth compartment mayinclude an agent for radiographic imaging. A cover of the kit mayinclude illustrations of the implanting procedure and a clear plasticcover may be placed over the compartments to maintain sterility.

Administration

In various embodiments, the analgesic agent and the anti-inflammatoryagent may be parenterally administered. The term “parenteral” as usedherein refers to modes of administration, which bypass thegastrointestinal tract, and include for example, intravenous,intramuscular, continuous or intermittent infusion, intraperitoneal,intrasternal, subcutaneous, intra-operatively, intrathecally,intradiskally, peridiskally, epidurally, perispinally, intraarticularinjection or combinations thereof.

Parenteral administration may additionally include, for example, aninfusion pump that administers a pharmaceutical composition (e.g.,analgesic and anti-inflammatory combination) through a catheter near thespine or one or more inflamed joints, an implantable mini-pump that canbe inserted at or near the target site, an implantable controlledrelease device or sustained release delivery system that can release acertain amount of the composition per hour or in intermittent bolusdoses. One example of a suitable pump for use is the SynchroMed®(Medtronic, Minneapolis, Minn.) pump. This pump has three sealedchambers. One contains an electronic module and battery. The secondcontains a peristaltic pump and drug reservoir. The third contains aninert gas, which provides the pressure needed to force thepharmaceutical composition into the peristaltic pump. To fill the pump,the pharmaceutical composition is injected through the reservoir fillport to the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously, atspecific times, or at set intervals between deliveries.

Potential drug delivery devices suitable for adaptation for the methodsdescribed herein include but are not limited to those described, forexample, in U.S. Pat. No. 6,551,290 (assigned to Medtronic, the entiredisclosure is herein incorporated by reference), which describes amedical catheter for target specific drug delivery; U.S. Pat. No.6,571,125 (assigned to Medtronic, the entire disclosure is hereinincorporated by reference), which describes an implantable medicaldevice for controllably releasing a biologically active agent; U.S. Pat.No. 6,594,880 (assigned to Medtronic, the entire disclosure is hereinincorporated by reference), which describes an intraparenchymal infusioncatheter system for delivering therapeutic agents to selected sites inan organism; and U.S. Pat. No. 5,752,930 (assigned to Medtronic, theentire disclosure is herein incorporated by reference), which describesan implantable catheter for infusing equal volumes of agents to spacedsites. In various embodiments, pumps may be adapted with apre-programmable implantable apparatus with a feedback regulateddelivery, a micro-reservoir osmotic release system for controlledrelease of chemicals, small, light-weight devices for delivering liquidmedication, implantable microminiature infusion devices, implantableceramic valve pump assemblies, or implantable infusion pumps with acollapsible fluid chamber. Alzet® osmotic pumps (Durect Corporation,Cupertino, Calif.) are also available in a variety of sizes, pumpingrates, and durations suitable for use in the described methods. Invarious embodiments, a method for delivering a therapeutic agent at ornear the target tissue site of a patient is provided. The methodcomprising inserting a cannula at or near a target tissue site andimplanting the drug depot at the target site beneath the skin of thepatient and brushing, dripping, injecting, or painting the gel in thetarget site to hold or have the drug depot adhere to the target site. Inthis way unwanted migration of the drug depot away from the target siteis reduced or eliminated.

In various embodiments, because the combination of analgesic andanti-inflammatory agent is locally administered, therapeuticallyeffective doses may be less than doses administered by other routes(oral, topical, etc.). In turn, systemic side effects, such as forexample, liver transaminase elevations, hepatitis, liver failure,myopathy, constipation, etc. may be reduced or eliminated.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target tissuesite and the gel administered (e.g., brushed, dripped, injected, orpainted, etc.) at or near the target site. In those embodiments wherethe drug depot is separate from the gel, first the cannula or needle canbe inserted through the skin and soft tissue down to the site ofinjection and one or more base layer(s) of gel can be administered tothe target site. Following administration of the one or more baselayer(s), the drug depot can be implanted on or in the base layer(s) sothat the gel can hold the depot in place or reduce migration. Ifrequired a subsequent layer or layers of gel can be applied on the drugdepot to surround the depot and further hold it in place. Alternatively,the drug depot may be implanted first and then the gel placed (e.g.,brushed, dripped, injected, or painted, etc.) around the drug depot tohold it in place. By using the gel, accurate and precise implantation ofa drug depot can be accomplished with minimal physical and psychologicaltrauma to the patient. The gel also avoids the need to suture the drugdepot to the target site reducing physical and psychological trauma tothe patient.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through the cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

FIG. 4 illustrates a number of common locations within a patient thatmay be sites at which inflammation and/or pain may occur. It will berecognized that the locations illustrated in FIG. 4 are merely exemplaryof the many different locations within a patient that may be the sitesof inflammation and/or pain. For example, inflammation and/or pain mayoccur at a patient's knees 21, hips 22, fingers 23, thumbs 24, neck 25,and spine 26.

One exemplary embodiment where the depot is suitable for use in painmanagement due to inflammation is illustrated in FIG. 5. Schematicallyshown in FIG. 5 is a dorsal view of the spine and sites where the drugdepot may be inserted using a cannula or needle beneath the skin 34 to aspinal site 32 (e.g., spinal disc space, spinal canal, soft tissuesurrounding the spine, nerve root, etc.) and one or more drug depots 28and 32 are delivered to various sites along the spine. In this way, whenseveral drug depots are to be implanted, they are implanted in a mannerthat optimizes location, accurate spacing, and drug distribution.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including, but notlimited to, at least one muscle, ligament, tendon, cartilage, spinaldisc, spinal foraminal space, near the spinal nerve root, or spinalcanal.

The at least one analgesic agent and at least one anti-inflammatoryagent-based formulation may be used to form different pharmaceuticalpreparations (e.g., drug depots, injectable formulations, etc.). Thepharmaceutical preparations may be formed in an administration with asuitable pharmaceutical carrier that may be solid or liquid, and placedin the appropriate form for parenteral or other administration asdesired. As persons of ordinary skill are aware, known carriers includebut are not limited to water, gelatin, lactose, starches, stearic acid,magnesium stearate, sicaryl alcohol, talc, vegetable oils, benzylalcohols, gums, waxes, propylene glycol, polyalkylene glycols and otherknown carriers.

Another embodiment provides a method for treating a mammal sufferingfrom inflammation and/or pain, said method comprising administering atherapeutically effective amount of at least one analgesic agent and atleast one anti-inflammatory agent at a target site beneath the skin ator near the target site. The at least one analgesic agent and at leastone anti-inflammatory agent may for example be administered locally tothe target tissue site as a drug depot.

In some embodiments, the therapeutically effective dosage amount and therelease rate profile are sufficient to reduce inflammation and/or painfor a period of at least one day, for example, 1-90 days, 1-10 days, 1-3days, 3-7 days, 3-12 days; 3-14 days, 7-10 days, 7-14 days, 7-21 days,7-30 days, 7-50 days, 7-90 days, 7-140 days, or 14-140 days.

In some embodiments the at least one analgesic agent and at least oneanti-inflammatory agent or a portion of the at least one analgesic agentand at least one anti-inflammatory agent are administered as a bolusdose at the target tissue to provide an immediate release of the atleast one analgesic agent and at least one anti-inflammatory agent.

In some embodiments there is a composition useful for the treatment ofinflammation comprising an effective amount of at least one analgesicagent and at least one anti-inflammatory agent that is capable of beingadministered to e.g., a pain or inflammatory site. By way of example,they may be administered locally to the foraminal spine, the epiduralspace or the intrathecal space of a spinal cord. Exemplaryadministration routes include but are not limited to catheter drugpumps, one or more local injections, polymer releases or combinationsthereof.

In some embodiments, the at least one analgesic agent and at least oneanti-inflammatory agent are administered parenterally, e.g., byinjection. In some embodiments, the injection is intrathecal, whichrefers to an injection into the spinal canal (intrathecal spacesurrounding the spinal cord). An injection may also be into a muscle orother tissue. In other embodiments, the analgesic agent and theanti-inflammatory agent is administered by placement into an openpatient cavity during surgery.

In some embodiments, the formulation is implantable at or near a targettissue site at the time of surgery. The active ingredients may then bereleased from the depot via diffusion in a sustained fashion over aperiod of time, e.g., 3-15 days, 5-10 days or 7-10 days post surgery inorder to address pain and inflammation.

In some embodiments, a desired release profile is maintained for atleast three days, at least ten days, at least twenty days, at leastthirty days, at least forty days, at least fifty days, at least ninetydays, at least one hundred days, at least one-hundred and thirty-fivedays, at least one-hundred and fifty days, or at least one hundred andeighty days.

In some embodiments, the drug depot may release 5%, 10%, 15%, 20%, 25%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the at least oneanalgesic agent or pharmaceutically acceptable salt thereof and at leastone anti-inflammatory agent or pharmaceutically acceptable salt thereofrelative to a total amount of at least one analgesic agent orpharmaceutically acceptable salt thereof and at least oneanti-inflammatory agent loaded in the drug depot over a period of atleast three days, at least seven days, at least ten days, at leasttwenty days, at least thirty days, at least forty days, at least fiftydays, at least ninety days, at least one hundred days, at leastone-hundred and thirty-five days, at least one-hundred and fifty days,or at least one hundred and eighty days. In various embodiments, theanalgesic will be released in an initial burst dose, then the analgesicwill be released daily for 3 days and then stop (e.g., this will besuitable to reduce, prevent or treat, post-operative pain), while theanti-inflammatory agent will be released daily without a burst dose for3 to 12 days, 5 to 10 days or 7 to 10 days after the drug depot isadministered to the target tissue site.

In various embodiments, an implantable drug depot useful for reducing,preventing or treating pain and inflammation is provided in a patient inneed of such treatment, the implantable drug depot comprising atherapeutically effective amount of an analgesic and ananti-inflammatory agent or pharmaceutically acceptable salts thereof,the depot being implantable at a site beneath the skin to reduce,prevent or treat pain and/or inflammation, wherein the drug depot (i)comprises one or more immediate release layer(s) that is capable ofreleasing about 5% to about 20% of the analgesic and theanti-inflammatory agent or pharmaceutically acceptable salts thereofrelative to a total amount of the analgesic and the anti-inflammatoryagent or pharmaceutically acceptable salts thereof loaded in the drugdepot over a first period of up to 48 hours and (ii) one or more sustainrelease layer(s) that is capable of releasing about 21% to about 99% ofthe analgesic and the anti-inflammatory agent or pharmaceuticallyacceptable salts thereof relative to a total amount of the analgesic andthe anti-inflammatory agent or pharmaceutically acceptable salts thereofloaded in the drug depot over a subsequent period of up to 3 days to 6months or 3 days to 2 weeks.

By way of non-limiting example, the target tissue site may comprise atleast one muscle, ligament, tendon, cartilage, spinal disc, spinalforaminal space near the spinal nerve root, facet or spinal canal. Thetarget tissue may be associated with an acute disease or chronic diseaseor surgery.

In some embodiments, the at least one analgesic agent orpharmaceutically acceptable salt thereof and at least oneanti-inflammatory agent or pharmaceutically acceptable salt thereof isencapsulated in a plurality of depots comprising microparticles,microspheres, microcapsules, and/or microfibers suspended in a gel.

In some embodiments, an implantable drug depot is provided, wherein thedrug depot (i) comprises one or more immediate release layer(s) thatreleases a bolus dose of at least one analgesic agent orpharmaceutically acceptable salt thereof and at least oneanti-inflammatory agent or pharmaceutically acceptable salt thereof at asite beneath the skin and (ii) one or more sustain release layer(s) thatreleases an effective amount of at least one analgesic agent orpharmaceutically acceptable salt thereof and at least oneanti-inflammatory agent or pharmaceutically acceptable salt thereof overa period of 3 days to 6 months. By way of example, in the drug depot,the one or more immediate release layer(s) may comprise poly(lactide-co-glycolide) (PLGA) and the one or more sustain releaselayer(s) may comprise polylactide (PLA).

Method of Making

In various embodiments, the drug depot comprising the active ingredientscan be made by combining a biocompatible polymer and a therapeuticallyeffective amount of the active ingredients or pharmaceuticallyacceptable salts thereof and forming the implantable drug depot from thecombination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: other therapeutic agent(s) andother optional additives such as radiographic agent(s), etc. indissolved or dispersed form. This results in a polymeric matrix regioncontaining these species after solvent removal. In other embodiments, asolution containing solvent with dissolved or dispersed therapeuticagent is applied to a pre-existing polymeric region, which can be formedusing a variety of techniques including solution processing andthermoplastic processing techniques, whereupon the therapeutic agent isimbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: the activeingredients, optional additional therapeutic agent(s), radiographicagent(s), and so forth. The resulting mixture is then shaped into animplantable drug depot. The mixing and shaping operations may beperformed using any of the conventional devices known in the art forsuch purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, certain therapeutic agents may undergosubstantial degradation under ordinary thermoplastic processingconditions. Hence, processing is preferably performed under modifiedconditions, which prevent the substantial degradation of the therapeuticagent(s). Although it is understood that some degradation may beunavoidable during thermoplastic processing, degradation is generallylimited to 10% or less. Among the processing conditions that may becontrolled during processing to avoid substantial degradation of thetherapeutic agent(s) are temperature, applied shear rate, applied shearstress, residence time of the mixture containing the therapeutic agent,and the technique by which the polymeric material and the therapeuticagent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the active ingredient containing drug depot.Conversely, in another embodiment, the biocompatible polymer can beprecompounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This precompounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., clonidine), invarious embodiments, the PGLA or PLA can be premixed with theradio-opacifying agent at temperatures of about, for example, 150° C. to170° C. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the therapeutic agent(s). For instance, the therapeuticagent and premixed composition can be mixed/compounded using a twinscrew extruder at substantially lower temperatures (e.g., 100-105° C.),and using substantially reduced volumetric output (e.g., less than 30%of full capacity, which generally corresponds to a volumetric output ofless than 200 cc/min). It is noted that this processing temperature iswell below the melting points of certain active ingredients, such as ananti-inflammatory and analgesic because processing at or above thesetemperatures will result in substantial therapeutic agent degradation.It is further noted that in certain embodiments, the processingtemperature will be below the melting point of all bioactive compoundswithin the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion processes may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet, strip, etc.) is cooled. Examples of coolingprocesses include air cooling and/or immersion in a cooling bath. Insome embodiments, a water bath is used to cool the extruded depot.However, where a water-soluble therapeutic agent such as activeingredients are used, the immersion time should be held to a minimum toavoid unnecessary loss of therapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.Thus, a sustained release region of the drug depot may, in variousembodiments, be made by immediately removal of water or moisture.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, active ingredients are used andmixed or sprayed with the PLGA or PEG550 polymer, and the resultingdepot may be formed by extrusion and dried.

The drug depot may also comprise combining a biocompatible polymer and atherapeutically effective amount of at least one analgesic agent orpharmaceutically acceptable salt thereof and at least oneanti-inflammatory agent or pharmaceutically acceptable salt thereof andforming the implantable drug depot from the combination.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. A plurality of implantable drug depots useful forreducing, preventing or treating pain and/or inflammation in a patientin need of such treatment, the plurality of drug depots comprising afirst set of one or more drug depots capable of releasing atherapeutically effective bolus dose of an analgesic and/or ananti-inflammatory agent or pharmaceutically acceptable salts thereof ata site beneath the skin and a second set of one or more drug depotscapable of releasing a therapeutically effective amount of the analgesicand/or the anti-inflammatory agent or pharmaceutically acceptable saltsthereof over a period of at least three days, the first set of one ormore drug depots and the second set of one or more drug depots beingsolid and separate from each other and the second set of one or moredrug depots comprises a polymer having an average molecular weight ofbetween about 10,000 to 100,000, wherein the analgesic comprisesalfentanil, butorphanol, codeine, fentanyl, hydromorphone, levorphanol,meperidine, morphine, sufentanil, tramadol or a combination thereof, andthe anti-inflammatory agent comprises clonidine, fluocinolone,dexamethasone, sulindac, sulfasalazine or a combination thereof, andwherein each depot of the first and second set comprises a pore formingagent that is dextrose in an amount of less than 20% of the weight ofthe polymer, and each depot of the first and second set comprises anadherent gel comprising a polyethylene glycol (PEG) conjugate or a PEGviscosity enhancing agent, wherein the gel stiffens after delivery to atarget site having a pre-dosed modulus of elasticity of about 1×10⁴ toabout 3×10⁵ dynes/cm² and a post-dosed modulus of elasticity of about1×10⁵ to about 7×10⁵ dynes/cm².
 2. A plurality of implantable drugdepots according to claim 1, wherein at least one of the second set ofdrug depot releases the analgesic and/or an anti-inflammatory over aperiod of 3 days to 6 months.
 3. A plurality of implantable drug depotsaccording to claim 1, wherein at least one of the second set of drugdepot releases the analgesic and/or an anti-inflammatory over a periodof 3 days to 2 weeks.
 4. A plurality of implantable drug depotsaccording to claim 1, wherein the one or more drug depots of the firstset releases a bolus dose of an analgesic and anti-inflammatory agent.5. A plurality of implantable drug depots according to claim 1, whereinthe first and second set of the drug depots further comprise one or morepolymer layers containing the analgesic and/or the anti-inflammatoryagent.
 6. A plurality of implantable drug depots according to claim 1,wherein each drug depot of the first and second sets further comprisesat least one biodegradable polymer comprising one or more ofpoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-ε-caprolactone,D,L-lactide-glycolide-ε-caprolactone caprolactone,glycolide-caprolactone, poly(glycolide-,-caprolactone) or a combinationthereof.
 7. A plurality of implantable drug depots according to claim 1,wherein each drug depot of the first or second set further comprises apolymer and the polymer comprises about 20 wt % to about 90 wt % of thedrug depot.
 8. A plurality of implantable drug depots according to claim1, wherein at least one drug depot releases about 20% to about 99% ofthe analgesic and/or the anti-inflammatory agent or pharmaceuticallyacceptable salts thereof relative to a total amount of the analgesicand/or the anti-inflammatory agent or pharmaceutically acceptable saltsthereof loaded in the drug depot over a period of 3 days to 6 monthsafter the drug depot is administered to a target tissue site.
 9. Aplurality of implantable drug depots according to claim 1, wherein theanalgesic and/or the anti-inflammatory agent or pharmaceuticallyacceptable salts thereof are encapsulated in each drug depot asmicrospheres, microcapsules, and/or microfibers suspended in the gel.10. A plurality of implantable drug depots according to claim 1, whereineach drug depot is in the form of one or more pellets.
 11. A kitcomprising a plurality of implantable drug depots useful for reducing,preventing or treating pain and/or inflammation in a patient in need ofsuch treatment, the kit comprising: an adherent gel that is part of atwo-component delivery system and when the two components are mixed, achemical process is activated to form the gel and cause the gel toadhere to the target tissue; a first set of the plurality of drug depotscapable of releasing a therapeutically effective bolus dose of ananalgesic and/or an anti-inflammatory agent or pharmaceuticallyacceptable salts thereof at a site beneath the skin; and a second set ofthe plurality of drug depots capable of releasing a therapeuticallyeffective amount of the analgesic and/or the anti-inflammatory agent orpharmaceutically acceptable salts thereof over a period of at leastthree days, the first set of one or more drug depots and the second setof one or more drug depots being solid and separate from each other andthe second set of one or more drug depots comprises a polymer having anaverage molecular weight of between about 10,000 to 100,000, wherein theanalgesic comprises alfentanil, butorphanol, codeine, fentanyl,hydromorphone, levorphanol, meperidine, morphine, sufentanil, tramadolor a combination thereof, and the anti-inflammatory agent comprisesclonidine, fluocinolone, dexamethasone, sulindac, sulfasalazine or acombination thereof, and wherein each depot of the first and second setcomprises a pore forming agent that is dextrose in an amount of lessthan 20% of the weight of the polymer and the adherent gel comprises apolyethylene glycol (PEG) conjugate or a PEG viscosity enhancing agent,wherein the gel stiffens after delivery to a target site having apre-dosed modulus of elasticity of about 1×10⁴ to about 3×10⁵ dynes/cm²and a post-dosed modulus of elasticity of about 1×10⁵ to about 7×10⁵.12. A kit according to claim 11, wherein the second set of the pluralityof drug depots releases the analgesic and/or an anti-inflammatory over aperiod of 3 days to 6 months.
 13. A kit according to claim 11, whereinthe second set of the plurality of drug depots releases the analgesicand/or an anti-inflammatory over a period of 3 days to 2 weeks.
 14. Akit according to claim 11, wherein the first set of the plurality ofdrug depots releases a bolus amount of analgesic.
 15. A kit according toclaim 11, wherein the first set of the plurality of drug depots releasesa bolus amount of anti-inflammatory agent.
 16. A plurality ofimplantable drug depots according to claim 1, wherein the pre-dosedmodulus of elasticity is about 5×10⁴ to about 1×10⁵ dynes/cm² and thepost-dosed modulus of elasticity is about 2×10⁵ to about 5×10⁵dynes/cm².